Anthrax lethal toxin, produced by the bacterium Bacillus anthracis, is
the major cause of death in animals infected with anthrax. One compon
ent of this toxin, lethal factor (LF), is suspected to be a metallopro
tease, but no physiological substrates have been identified. Here it i
s shown that LF is a protease that cleaves the amino terminus of mitog
en-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and th
at this cleavage inactivates MAPKK1 and inhibits the MAPK signal trans
duction pathway. The identification of a cleavage site for LF may faci
litate the development of LF inhibitors.